2. Academic Validation
  3. Targeted inhibition of FBXL2 confers susceptibility of HER2-negative breast cancer to trastuzumab deruxtecan

Targeted inhibition of FBXL2 confers susceptibility of HER2-negative breast cancer to trastuzumab deruxtecan

  • Nat Cancer. 2026 Feb;7(2):334-351. doi: 10.1038/s43018-025-01112-z.
Jing Xu # 1 2,  Jing Liu # 3,  Yang Liu # 1,  Ting Huang 4,  Yong Yi 1,  Ruixiao Bai 1,  Haorui Zheng 1,  Xiaoli Chen 1,  Jiexin Gao 1,  Xin Lian 1,  Rongtian Guo 1,  Chuan Xu 4,  Qintong Li 5,  Yujun Zhang 1,  Yang Cao 6,  Peng Mi 7,  Zhi-Xiong Jim Xiao 8 9 10,  Mengmeng Niu 11
Affiliations

Affiliations

  • 1 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
  • 2 Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 3 Department of Radiology, Huaxi MR Research Center (HMRRC), State Key Laboratory of Biotherapy, West China Hospital, and College of Polymer Science and Engineering, Sichuan University, Chengdu, China.
  • 4 Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
  • 5 Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 6 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. [email protected].
  • 7 Department of Radiology, Huaxi MR Research Center (HMRRC), State Key Laboratory of Biotherapy, West China Hospital, and College of Polymer Science and Engineering, Sichuan University, Chengdu, China. [email protected].
  • 8 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. [email protected].
  • 9 Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [email protected].
  • 10 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 11 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. [email protected].
  • # Contributed equally.
PMID: 41612000 DOI: 10.1038/s43018-025-01112-z
Abstract

Trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate, has transformed treatment for HER2-expressing solid tumors. However, heterogeneous intratumoral HER2 expression, particularly high densities of HER2-immunohistochemistry score 0 (HER2-IHC 0) cells, limits its clinical efficacy. Here, we discovered that targeted inhibition of F-box protein FBXL2 elevates HER2 expression on the plasma membrane of HER2-IHC 0 triple-negative breast Cancer (TNBC) cells, thereby sensitizing them to T-DXd. Mechanistically, FBXL2 promotes HER2 polyubiquitination at K747 and proteasomal degradation. Notably, small molecules GGTi-2418 and ketoconazole effectively elevate HER2 expression via blocking FBXL2 membrane localization. We further developed lipid nanoparticles (LNPs) to encapsulate GGTi-2418 and ketoconazole, enabling their enrichment in TNBC tumors. Strikingly, GGTi-2418@LNP or ketoconazole@LNP combined with T-DXd induced robust and durable tumor regression in HER2-IHC 0 TNBC xenograft models in female mice. Together, this study highlights that targeted inhibition of FBXL2 combined with T-DXd may be a viable therapeutic strategy for treating HER2-IHC 0 solid tumors.

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